The risk of most cancers, including leukemias, increases exponentially as we age, with over 90% of cancers occurring after the age of 50. This association has been primarily ascribed to the gradual accumulation of mutations throughout life. We contend that the contribution of mutations (while necessary) is not sufficient to explain the role of aging in the development of leukemias and other cancers. Just as species evolution has been driven by environmental changes that select for adaptive phenotypes in populations, we propose that the changes in our tissues known to occur in old age are substantial contributors to oncogenesis. Inflammation and senescent cells increase in the bone marrow of the elderly, which along with other changes contribute to impaired hematopoiesis. We have used mouse models to show that the aged and inflammatory bone marrow microenvironment reduces the fitness of hematopoietic progenitors, promoting selection for particular adaptive oncogenic events, leading to increased leukemogenesis in these contexts. Here, we will develop interventions that modulate the bone marrow microenvironment to limit leukemogenesis. We will determine how both aging and developed interventions alter the bone marrow microenvironment and resident hematopoietic stem and progenitor cells, and how these changes influence selection for particular oncogenic events. Our central hypothesis is that aging-dependent increases in inflammation and senescent cells are critical for enhancing selection for oncogenic mutations that occur throughout life, and that dampening inflammation and/or removing senescent cells can reduce the risk of the associated leukemias. To test our hypothesis, we will pursue two aims: 1) develop interventions that can reverse the aging-associated promotion of leukemogenesis, and 2) identify and characterize the key aging-associated changes in the bone marrow that promote leukemogenesis. Beyond the avoidance of known carcinogens, we are unlikely to develop methods any time soon that can prevent the accumulation of most mutations that occur as we age. However, we can develop interventions that alter tissue microenvironments so as to reduce the selective value of oncogenic mutations, or otherwise provide a landscape less conducive to cancer development. Proposed studies will identify specific microenvironmental features that modulate the evolution of leukemia in the bone marrow, and should provide a proof-of-principle for whether safe and effective interventions can be developed to limit aging-associated oncogenesis.